The primary goal of this project is investigate specific defects in cerebral network excitability in the developing nervous system of a mutant mouse model of inherited generalized epilepsy, tottering. Inherited epilepsies of the spike-wave (SW) pattern comprise a major category of human seizure disorder with early childhood onset, but neither the underlying basic neuronal excitability mechanisms, nor the effects of SW on developing neural circuitry have been clearly defined. We propose to examine two specific excitability defects, a voltage-dependent prolongation of the paroxysmal depolarizing shift (PDS), and a norepinephrine-dependent reduction of the afterhyperpolarization (AHP), that are unmasked in hippocampal pyramidal neurons during potassium induced-bursting. We hypothesize: (1) that the altered tg excitability is a network defect resulting from aberrant rearrangements of synaptic inputs; (2) that two distinct candidate structural abnormalities found in the tg mutant brain (dentate granule cell-mossy fiber overgrowth and LC axon terminal hyperinnervation) may be linked, respectively, to the prolonged PDS and the reduced AHP; and (3) that the network excitability defects may also be present in thalamocortical circuits. Using intracellular recordings in the CA3 region of the in vitro hippocampal slice, we will test specific hypotheses regarding the membrane and synaptic mechanisms of this network defect, its functional role in epileptogenesis, and whether it arises developmentally as a primary cellular expression of the tg mutant locus, or secondarily as a product of seizure-induced neuroplasticity in the hippocampus, and whether it can be identified in other brain regions. In specific aim 1, we will analyze membrane properties of control and mutant neurons to detect intrinsic CA3 neuron defects. In specific aim 2, we will use selective agonists and antagonists to determine whether the reduced AHP during bursting is mediated by endogenous NE, and we will isolate neurons CA3 to determine whether the prolonged PDS is mediated by mossy fiber outgrowth, In specific aim 3, we will use developmental studies to examine the serial order of appearance of the excitability defects relative to the onsets of the two presynaptic axon terminal abnormalities. In specific aim 4, we will examine similar network excitability properties in a thalamocortical slice system. These studies will define epileptogenic cellular defects produced by the tg mutation, and provide new information about basic mechanisms of spike-wave seizures, the role of axon terminal hyperplasia in generalized epilepsy, and the degree of long-term cellular neuroplasticity that may accompany early seizures of the spike-wave pattern.